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W2149955916 abstract "Follicular thyroglobulin (TG) decreases expression of the thyroid-restricted transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, thereby suppressing expression of the sodium iodide symporter, thyroid peroxidase, TG, and thyrotropin receptor genes (Suzuki, K., Lavaroni, S., Mori, A., Ohta, M., Saito, J., Pietrarelli, M., Singer, D. S., Kimura, S., Katoh, R., Kawaoi, A., and Kohn, L. D. (1997) Proc. Natl. Acad. Sci. U. S. A. 95, 8251–8256). The ability of highly purified 27, 19, or 12 S follicular TG to suppress thyroid-restricted gene expression correlates with their ability to bind to FRTL-5 thyrocytes and is inhibited by a specific antibody to the thyroid apical membrane asialoglycoprotein receptor (ASGPR), which is related to the ASGPR of liver cells. Phosphorylating serine/threonine residues of TG, by autophosphorylation or protein kinase A, eliminates TG suppression and enhances transcript levels of the thyroid-restricted genes 2-fold in the absence of a change in TG binding to the ASGPR. Follicular TG suppression of thyroid-restricted genes is thus mediated by the ASPGR on the thyrocyte apical membrane and regulated by a signal system wherein phosphorylation of serine/threonine residues on the bound ligand is an important component. These data provide a hitherto unsuspected role for the ASGPR in transcriptional signaling, aside from its role in endocytosis. They establish a functional role for phosphorylated serine/threonine residues on the TG molecule. Follicular thyroglobulin (TG) decreases expression of the thyroid-restricted transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, thereby suppressing expression of the sodium iodide symporter, thyroid peroxidase, TG, and thyrotropin receptor genes (Suzuki, K., Lavaroni, S., Mori, A., Ohta, M., Saito, J., Pietrarelli, M., Singer, D. S., Kimura, S., Katoh, R., Kawaoi, A., and Kohn, L. D. (1997) Proc. Natl. Acad. Sci. U. S. A. 95, 8251–8256). The ability of highly purified 27, 19, or 12 S follicular TG to suppress thyroid-restricted gene expression correlates with their ability to bind to FRTL-5 thyrocytes and is inhibited by a specific antibody to the thyroid apical membrane asialoglycoprotein receptor (ASGPR), which is related to the ASGPR of liver cells. Phosphorylating serine/threonine residues of TG, by autophosphorylation or protein kinase A, eliminates TG suppression and enhances transcript levels of the thyroid-restricted genes 2-fold in the absence of a change in TG binding to the ASGPR. Follicular TG suppression of thyroid-restricted genes is thus mediated by the ASPGR on the thyrocyte apical membrane and regulated by a signal system wherein phosphorylation of serine/threonine residues on the bound ligand is an important component. These data provide a hitherto unsuspected role for the ASGPR in transcriptional signaling, aside from its role in endocytosis. They establish a functional role for phosphorylated serine/threonine residues on the TG molecule. thyrotropin thyroglobulin thyroid transcription factor thyrotropin receptor thyroid peroxidase sodium iodide symporter bovine serum albumin high pressure gel permeation chromatography insulin-like growth factor-1 major histocompatibility complex Tris-buffered saline with Tween 20 protein kinase A chloramphenicol acetyltransferase Thyrotropin (TSH),1 in concert with insulin and insulin-like growth factor-1 (IGF-1), regulates thyroid function (1Kohn L.D. Saji M. Akamizu T. Ikuyama S. Isozaki O. Kohn A.D. Santisteban P. Chan J.Y.C. Bellur S. Rotella C.M. Alvarez F.V. Aloj S.M. Adv. Exp. Med. Biol. 1989; 261: 151-210Crossref PubMed Scopus (13) Google Scholar, 2Vassart G. Dumont J.E. Endocr. Rev. 1992; 13: 596-611PubMed Google Scholar, 3Kohn L.D. Shimura H. Shimura Y. Hidaka A. Giuliani C. Napolitano G. Ohmori M. Laglia G. Saji M. Vitam. Horm. 1995; 50: 287-384Crossref PubMed Scopus (136) Google Scholar). TSH increases expression of the sodium iodide symporter (NIS), thyroglobulin (TG), and thyroid peroxidase (TPO) genes; this increases concentrative iodide uptake, TG synthesis, and thyroid hormone formation (1Kohn L.D. Saji M. Akamizu T. Ikuyama S. Isozaki O. Kohn A.D. Santisteban P. Chan J.Y.C. Bellur S. Rotella C.M. Alvarez F.V. Aloj S.M. Adv. Exp. Med. Biol. 1989; 261: 151-210Crossref PubMed Scopus (13) Google Scholar, 2Vassart G. Dumont J.E. Endocr. Rev. 1992; 13: 596-611PubMed Google Scholar, 3Kohn L.D. Shimura H. Shimura Y. Hidaka A. Giuliani C. Napolitano G. Ohmori M. Laglia G. Saji M. Vitam. Horm. 1995; 50: 287-384Crossref PubMed Scopus (136) Google Scholar, 4Dai G. Levy O. Carrasco N. Nature. 1996; 379: 458-460Crossref PubMed Scopus (956) Google Scholar). NIS, TG, and TPO expression are controlled by thyroid-restricted transcription factors: thyroid transcription factor (TTF)-1, TTF-2, and Pax-8 (5Guazzi S. Price M. De Felice M. Damante G. Mattei M.-G. Di Lauro R. EMBO J. 1990; 9: 3631-3639Crossref PubMed Scopus (469) Google Scholar, 6Mizuno K. Gonzalez F.J. Kimura S. Mol. Cell. Biol. 1991; 11: 4927-4933Crossref PubMed Scopus (124) Google Scholar, 7Francis-Lang H. Price M. Polycarpou-Schwarz M. Di Lauro R. Mol. Cell. Biol. 1992; 12: 576-588Crossref PubMed Scopus (208) Google Scholar, 8Zannini M. Francis-Lang H. Plachov D. Di Lauro R. Mol. Cell. Biol. 1992; 12: 4230-4241Crossref PubMed Scopus (271) Google Scholar, 9Zannini M. Avantaggiato V. Biffali E. Arnone M.I. Dato K. Pischetola M. Taylor B.A. Phillips S.J. Simeone A. Di Lauro R. EMBO J. 1997; 16: 3185-3197Crossref PubMed Scopus (217) Google Scholar, 10Ortiz L. Zannini M. Di Lauro R. Santisteban P. J. Biol. Chem. 1997; 272: 23334-23339Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 11Endo T. Kaneshige M. Nakazato M. Ohmori M. Harii N. Onaya T. Mol. Endocrinol. 1997; 11: 1747-1755PubMed Google Scholar, 12Ohno M. Zannini M. Levy O. Carrasco N. Di Lauro R. Mol. Cell. Biol. 1999; 19: 2051-29060Crossref PubMed Scopus (214) Google Scholar). TTF-2 is regulated by insulin/IGF-1 (9Zannini M. Avantaggiato V. Biffali E. Arnone M.I. Dato K. Pischetola M. Taylor B.A. Phillips S.J. Simeone A. Di Lauro R. EMBO J. 1997; 16: 3185-3197Crossref PubMed Scopus (217) Google Scholar, 10Ortiz L. Zannini M. Di Lauro R. Santisteban P. J. Biol. Chem. 1997; 272: 23334-23339Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar), TTF-1 and Pax-8 by TSH/cAMP (13Shimura H. Okajima F. Ikuyama S. Shimura Y. Kimura S. Saji M. Kohn L.D. Mol. Endocrinol. 1994; 8: 1049-1069Crossref PubMed Google Scholar, 14Shimura H. Shimura Y. Ohmori M. Ikuyama S. Kohn L.D. Mol. Endocrinol. 1995; 9: 527-539PubMed Google Scholar, 15Van Renterghem P. Vassart G. Cristophe D. Biochim. Biophys. Acta. 1996; 1307: 97-103Crossref PubMed Scopus (46) Google Scholar, 16Poleev A. Okladnova O. Musti A.M. Schneider S. Royer-Pokora B. Plachov D. Eur. J. Biochem. 1997; 247: 860-869Crossref PubMed Scopus (48) Google Scholar).We have recently shown that TG accumulated in the follicular lumen acts as a feedback suppressor of hormonally-increased thyroid function (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar, 18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar, 19Suzuki K. Mori A. Saito J. Ulianich L. Nakazato M. Kohn L.D. Endocrinology. 1999; (in press)Google Scholar). Thus, follicular TG selectively suppresses expression of TTF-1, TTF-2, and Pax-8 (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar, 18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar), thereby altering expression of the TG, TPO, NIS, and TSHR genes, and counter regulating TSH- and insulin/IGF-1-induced changes in these genes (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar, 18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar, 19Suzuki K. Mori A. Saito J. Ulianich L. Nakazato M. Kohn L.D. Endocrinology. 1999; (in press)Google Scholar). The follicular TG acts transcriptionally; its suppressive effect is not duplicated by thyroid hormones or iodide (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar, 18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar, 19Suzuki K. Mori A. Saito J. Ulianich L. Nakazato M. Kohn L.D. Endocrinology. 1999; (in press)Google Scholar). The mechanism by which follicular TG can act as a transcriptional suppressor is unknown.TG is synthesized as a 12 S molecule (330 kDa), but forms a 19 S dimer and 27 S tetramer; all three exist in the follicular lumen (20Salvatore G. Edelhoch H. Li C.H. Hormonal Proteins and Peptides. I. Academic Press, New York1973: 201-244Crossref Google Scholar, 21Dunn J. Braverman L.E. Utiger R.D. The Thyroid: A Fundamental and Clinical Text. Lippincott-Raven Publishers, Philadelphia1996: 85-95Google Scholar). It has been suggested that newly synthesized TG attaches to a specific binding protein related to the lectin-like asialoglycoprotein receptor (ASPGR) of the liver (22Consiglio E. Salvatore G. Rall J.E. Kohn L.D. J. Biol. Chem. 1979; 254: 5065-5076Abstract Full Text PDF PubMed Google Scholar, 23Consiglio E. Shifrin S. Yavin Z. Ambesi-Impiombato F.S. Rall J.E. Salvatore G. Kohn L.D. J. Biol. Chem. 1981; 256: 10592-10599Abstract Full Text PDF PubMed Google Scholar, 24Shifrin S. Kohn L.D. J. Biol. Chem. 1981; 256: 10600-10605Abstract Full Text PDF PubMed Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar, 26Pacifico F. Laviola L. Ulianich L. Porcellini A. Ventra C. Consiglio E. Avvedimento E.V. Biochem. Biophys. Res. Commun. 1995; 210: 138-144Crossref PubMed Scopus (31) Google Scholar) 2F. Pacifico, D. Liguoro, L. Ulianich, N. Montuori, G. Cali, L. Nitsch, L. D. Kohn, S. Formisano, and E. Consiglio, submitted for publication.2F. Pacifico, D. Liguoro, L. Ulianich, N. Montuori, G. Cali, L. Nitsch, L. D. Kohn, S. Formisano, and E. Consiglio, submitted for publication. and that the thyroid ASPGR vectorially transports newly synthesized TG to the follicular lumen (22Consiglio E. Salvatore G. Rall J.E. Kohn L.D. J. Biol. Chem. 1979; 254: 5065-5076Abstract Full Text PDF PubMed Google Scholar, 23Consiglio E. Shifrin S. Yavin Z. Ambesi-Impiombato F.S. Rall J.E. Salvatore G. Kohn L.D. J. Biol. Chem. 1981; 256: 10592-10599Abstract Full Text PDF PubMed Google Scholar, 24Shifrin S. Kohn L.D. J. Biol. Chem. 1981; 256: 10600-10605Abstract Full Text PDF PubMed Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar). During this vectorial transport process, TG undergoes posttranslational modifications, including phosphorylation, (21Dunn J. Braverman L.E. Utiger R.D. The Thyroid: A Fundamental and Clinical Text. Lippincott-Raven Publishers, Philadelphia1996: 85-95Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar, 28Eggo M.C. Drucker D. Cheifetz R. Burrow G. Can. J. Biochem. Cell Biol. 1983; 61: 662-669Crossref PubMed Scopus (9) Google Scholar, 29Yamamoto K. Tsuji T. Tarutani O. Oswaa T. Biochim. Biophys. Acta. 1985; 838: 84-92Crossref PubMed Scopus (31) Google Scholar, 30Spiro M.J. Gorski K.M. Endocrinology. 1986; 119: 1146-1158Crossref PubMed Scopus (20) Google Scholar, 31Consiglio E. Acquaviva A.M. Formisano S. Liguoro D. Gallo A. Vittorio T. Santisteban P. DeLuca M. Shifrin S. Yeh H.J.C. Kohn L.D. J. Biol. Chem. 1987; 262: 10304-10314Abstract Full Text PDF PubMed Google Scholar, 32Herzog V. Neumuller W. Holzmann B. EMBO J. 1987; 6: 5555-5560Crossref Scopus (58) Google Scholar). At the apical membrane, a membrane-bound sialotransferase and TPO are suggested to reiteratively sialylate and iodinate the TG, allowing its release from the ASGPR into the follicular lumen (22Consiglio E. Salvatore G. Rall J.E. Kohn L.D. J. Biol. Chem. 1979; 254: 5065-5076Abstract Full Text PDF PubMed Google Scholar, 23Consiglio E. Shifrin S. Yavin Z. Ambesi-Impiombato F.S. Rall J.E. Salvatore G. Kohn L.D. J. Biol. Chem. 1981; 256: 10592-10599Abstract Full Text PDF PubMed Google Scholar, 24Shifrin S. Kohn L.D. J. Biol. Chem. 1981; 256: 10600-10605Abstract Full Text PDF PubMed Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar). The ASGPR may also be indirectly involved in selective degradation of highly iodinated 19 S TG from the follicular lumen by a process termed “selective fluid pinocytosis” (22Consiglio E. Salvatore G. Rall J.E. Kohn L.D. J. Biol. Chem. 1979; 254: 5065-5076Abstract Full Text PDF PubMed Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar,33van den Hove M.F. Couvreur M. de Visscher M. Salvatore G. Eur. J. Biochem. 1982; 122: 415-422Crossref PubMed Scopus (38) Google Scholar). Thus, ASGPR binding of TG at the apical membrane is hypothesized to bind more recently synthesized, poorly iodinated, and poorly sialylated TG, sequestering it, and making it unavailable for fluid pinocytosis. As a result, highly iodinated and sialylated TG molecules, which are free in the follicular lumen, preferentially undergo fluid pinocytosis (22Consiglio E. Salvatore G. Rall J.E. Kohn L.D. J. Biol. Chem. 1979; 254: 5065-5076Abstract Full Text PDF PubMed Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar, 33van den Hove M.F. Couvreur M. de Visscher M. Salvatore G. Eur. J. Biochem. 1982; 122: 415-422Crossref PubMed Scopus (38) Google Scholar). TG bound to the ASGPR may, however, be internalized with receptor recycling (22Consiglio E. Salvatore G. Rall J.E. Kohn L.D. J. Biol. Chem. 1979; 254: 5065-5076Abstract Full Text PDF PubMed Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar, 33van den Hove M.F. Couvreur M. de Visscher M. Salvatore G. Eur. J. Biochem. 1982; 122: 415-422Crossref PubMed Scopus (38) Google Scholar).2 This is suggested to be the basis of the “last come-first served” concept, wherein the most recently synthesized TG attached to the receptor is the first to be degraded (20Salvatore G. Edelhoch H. Li C.H. Hormonal Proteins and Peptides. I. Academic Press, New York1973: 201-244Crossref Google Scholar, 22Consiglio E. Salvatore G. Rall J.E. Kohn L.D. J. Biol. Chem. 1979; 254: 5065-5076Abstract Full Text PDF PubMed Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar, 33van den Hove M.F. Couvreur M. de Visscher M. Salvatore G. Eur. J. Biochem. 1982; 122: 415-422Crossref PubMed Scopus (38) Google Scholar). ASGPR phosphorylation of serine/threonine residues has been related to ASGPR recycling in the liver, but not to endocytosis (34Schwartz A.L. Biochem. J. 1984; 223: 481-486Crossref PubMed Scopus (18) Google Scholar, 35Fallon R.J. Schwartz A.L. J. Biol. Chem. 1988; 263: 13159-13166Abstract Full Text PDF PubMed Google Scholar, 36Stoorvogel W. Schwartz A.L. Strous G.J. Fallon R.J. J. Biol. Chem. 1991; 266: 5438-5444Abstract Full Text PDF PubMed Google Scholar).In this report we show that the ability of different polymeric forms of TG to suppress thyroid-restricted gene expression is related to their ability to bind to the ASGPR, which has been separately located on the apical membrane of thyrocytes.2 In addition, we show that autophosphorylation of TG, which has been shown to be restricted to phosphoserine residues (37Alvino C.G. Acquaviva A.M. Catanzano A.M.M. Tassi V. Endocrinology. 1995; 136: 3179-3185Crossref PubMed Scopus (15) Google Scholar), not only eliminates the ability of TG to be a transcriptional suppressor of thyroid-restricted genes, it also allows the TG to act as an enhancer of their expression. Treatment of cells with an inhibitor of serine/threonine phosphatase activity, okadaic acid, also eliminates TG suppression. We suggest that follicular TG acts as a regulator of thyroid-restricted gene expression by binding to the ASGPR on the apical thyrocyte membrane and that phosphorylation of TG regulates the suppressive effect. The data are the first to describe a role for the ASGPR in transcriptional signaling and a biologic role for phosphorylated TG, particularly its phosphoserine residues.DISCUSSIONThe thyroid follicle is the functional unit of the thyroid gland (1Kohn L.D. Saji M. Akamizu T. Ikuyama S. Isozaki O. Kohn A.D. Santisteban P. Chan J.Y.C. Bellur S. Rotella C.M. Alvarez F.V. Aloj S.M. Adv. Exp. Med. Biol. 1989; 261: 151-210Crossref PubMed Scopus (13) Google Scholar, 2Vassart G. Dumont J.E. Endocr. Rev. 1992; 13: 596-611PubMed Google Scholar, 3Kohn L.D. Shimura H. Shimura Y. Hidaka A. Giuliani C. Napolitano G. Ohmori M. Laglia G. Saji M. Vitam. Horm. 1995; 50: 287-384Crossref PubMed Scopus (136) Google Scholar, 20Salvatore G. Edelhoch H. Li C.H. Hormonal Proteins and Peptides. I. Academic Press, New York1973: 201-244Crossref Google Scholar, 21Dunn J. Braverman L.E. Utiger R.D. The Thyroid: A Fundamental and Clinical Text. Lippincott-Raven Publishers, Philadelphia1996: 85-95Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar, 49Field J.B. Ingbar S.H. Braverman L.E. Werner's The Thyroid: A Fundamental and Clinical Text. 5th Ed. J. B. Lippincott Co., Philadelphia1986: 288-303Google Scholar). Thyroid cells secrete and store TG into its lumen; they also concentrate and secrete iodide into the follicular lumen, where TPO and H2O2 iodinate the TG tyrosine residues and contribute to iodotyrosine coupling to form thyroid hormones. Thyroid hormones are secreted into the blood stream, after TG is transported to lysosomes and degraded. This complex process is controlled by TSH and insulin/IGF-1 (1Kohn L.D. Saji M. Akamizu T. Ikuyama S. Isozaki O. Kohn A.D. Santisteban P. Chan J.Y.C. Bellur S. Rotella C.M. Alvarez F.V. Aloj S.M. Adv. Exp. Med. Biol. 1989; 261: 151-210Crossref PubMed Scopus (13) Google Scholar, 2Vassart G. Dumont J.E. Endocr. Rev. 1992; 13: 596-611PubMed Google Scholar, 3Kohn L.D. Shimura H. Shimura Y. Hidaka A. Giuliani C. Napolitano G. Ohmori M. Laglia G. Saji M. Vitam. Horm. 1995; 50: 287-384Crossref PubMed Scopus (136) Google Scholar, 20Salvatore G. Edelhoch H. Li C.H. Hormonal Proteins and Peptides. I. Academic Press, New York1973: 201-244Crossref Google Scholar, 21Dunn J. Braverman L.E. Utiger R.D. The Thyroid: A Fundamental and Clinical Text. Lippincott-Raven Publishers, Philadelphia1996: 85-95Google Scholar, 25Kohn L.D. De Luca M. Santisteban P. Shifrin S. Yeh H.J.C. Formisano S. Consiglio E. Eggo M. Burrow G. Progress in Endocrine Research and Therapy; Thyroglobulin: The Prothyroid Hormone. 2. Raven Press, New York1985: 171-214Google Scholar, 50Santisteban P. Kohn L.D. Di Lauro R. J. Biol. Chem. 1987; 262: 4048-4052Abstract Full Text PDF PubMed Google Scholar). TSH and insulin/IGF-1 regulate the expression and activity of the thyroid-restricted transcription factors, TTF-1, TTF-2, and Pax-8, which are critical for the thyroid-restricted expression of the TG, TPO, and NIS genes (10Ortiz L. Zannini M. Di Lauro R. Santisteban P. J. Biol. Chem. 1997; 272: 23334-23339Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 11Endo T. Kaneshige M. Nakazato M. Ohmori M. Harii N. Onaya T. Mol. Endocrinol. 1997; 11: 1747-1755PubMed Google Scholar, 12Ohno M. Zannini M. Levy O. Carrasco N. Di Lauro R. Mol. Cell. Biol. 1999; 19: 2051-29060Crossref PubMed Scopus (214) Google Scholar, 13Shimura H. Okajima F. Ikuyama S. Shimura Y. Kimura S. Saji M. Kohn L.D. Mol. Endocrinol. 1994; 8: 1049-1069Crossref PubMed Google Scholar, 14Shimura H. Shimura Y. Ohmori M. Ikuyama S. Kohn L.D. Mol. Endocrinol. 1995; 9: 527-539PubMed Google Scholar, 15Van Renterghem P. Vassart G. Cristophe D. Biochim. Biophys. Acta. 1996; 1307: 97-103Crossref PubMed Scopus (46) Google Scholar, 16Poleev A. Okladnova O. Musti A.M. Schneider S. Royer-Pokora B. Plachov D. Eur. J. Biochem. 1997; 247: 860-869Crossref PubMed Scopus (48) Google Scholar).Each thyrocyte is faced with the same levels of TSH and insulin/IGF-1 in the blood stream, yet the functional state of each follicle varies (18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar, 19Suzuki K. Mori A. Saito J. Ulianich L. Nakazato M. Kohn L.D. Endocrinology. 1999; (in press)Google Scholar, 51Yamamoto K. Kato Y. Matsumoto H. Moriyama S.I. Kawaoi A. Acta Histochem. Cytochem. 1988; 21: 455-461Crossref Scopus (6) Google Scholar, 52Studer H. Peter H.J. Gerber H. Endocr. Rev. 1989; 10: 125-135Crossref PubMed Scopus (196) Google Scholar, 53Baptist M. Pohl V. Dumont J.E. Roger P.P. Thyroidology. 1991; 3: 109-113PubMed Google Scholar, 54Suzuki K. Katoh R. Kawaoi A. Acta Histochem. Cytochem. 1992; 25: 13-21Crossref Scopus (46) Google Scholar). Some have high levels of TG and thyroid hormones in their follicular lumen, exhibit high levels of TPO activity, and are surrounded by metabolically active columnar epithelial cells; others are nearly devoid of TG, TPO, and thyroid hormones and are surrounded by flattened and quiescent thyroid cells (18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar, 19Suzuki K. Mori A. Saito J. Ulianich L. Nakazato M. Kohn L.D. Endocrinology. 1999; (in press)Google Scholar, 51Yamamoto K. Kato Y. Matsumoto H. Moriyama S.I. Kawaoi A. Acta Histochem. Cytochem. 1988; 21: 455-461Crossref Scopus (6) Google Scholar, 52Studer H. Peter H.J. Gerber H. Endocr. Rev. 1989; 10: 125-135Crossref PubMed Scopus (196) Google Scholar, 53Baptist M. Pohl V. Dumont J.E. Roger P.P. Thyroidology. 1991; 3: 109-113PubMed Google Scholar, 54Suzuki K. Katoh R. Kawaoi A. Acta Histochem. Cytochem. 1992; 25: 13-21Crossref Scopus (46) Google Scholar). Recent studies suggest that TG accumulated in the follicular lumen partially explains the heterogeneity of follicular function (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar, 18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar). Thus, purified follicular TG can suppress TSH and insulin/IGF-1 increased TTF-1, TTF-2, and Pax-8 expression and suppress, in turn, TSH or insulin/IGF-1-increased TG, TPO, and NIS gene expression as well as activity (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar, 18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar, 19Suzuki K. Mori A. Saito J. Ulianich L. Nakazato M. Kohn L.D. Endocrinology. 1999; (in press)Google Scholar). The effect was very specific. It was not duplicated by iodide or thyroid hormones (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar, 18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar), did not involve ubiquitous transcription factors which also regulated the TSHR, TG, or TPO genes (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar), and actually increased expression of MHC class I, which is ubiquitously expressed on most cells in the organism (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar).In this new paradigm of thyroid control, TSH, insulin, and/or IGF-1 enhanced thyroid-restricted gene expression and function; follicular TG, a critical product of thyroid-restricted gene expression, acted as a feedback regulator of the hormonal induced increase (17Suzuki K. Lavaroni S. Mori A. Ohta M. Saito J. Pietrarelli M. Singer D.S. Kimura S. Katoh R. Kawaoi A. Kohn L.D. Proc. Natl. Acad. Sci. U. S. A. 1997; 95: 8251-8256Crossref Scopus (119) Google Scholar, 18Suzuki K. Mori A. Lavaroni S. Miyagi E. Ulianich L. Katoh R. Kawaoi A. Kohn L.D. Thyroid. 1999; 9: 319-331Crossref PubMed Scopus (48) Google Scholar, 19Suzuki K. Mori A. Saito J. Ulianich L. Nakazato M. Kohn L.D. Endocrinology. 1999; (in press)Google Scholar). TSH reinitiated the hormone-induced synthetic phase of follicle function by inducing fluid pinocytosis and TG degradation, a rapid phenomenon relative to the TSH and insulin/IGF-1-initiated synthetic phase of follicular function (55Suzuki K. Mori A. Lavaroni S. Katoh R. Kohn L.D. Kawaoi A. Acta Histochem Cytochem. 1999; 32: 111-119Crossref Scopus (18) Google Scholar). The fundamental question that arose from this new paradigm is how the TG molecule stored in the follicular lumen, could regulate the transcriptional machinery of the cell.In the present report, we show that binding of TG to the ASGPR on the apical membrane of the thyrocyte, the membrane facing the follicular lumen, is the initial event in the TG suppression process in thyrocytes. We show that 27 S TG binds to thyroid cells better than 19 S or 12 S TG and that this parallels the suppressive action of the follicular TG moieties, 27 S > 19 S > 12 S. We show that a specific antibody to the RHL-1 subunit of the thyroid ASGPR2 blocks TG-induced suppression. We show that neuraminidase treatment of cells blocks suppression just as it blocks ASGPR-mediated endocytosis and binding (22Consiglio E. Salvatore G. Rall J.E. Kohn L.D. J. Biol. Chem. 1979; 254: 5065-5076Abstract Full Text PDF PubMed Google Scholar, 42Paulson J.C. Hill R.L. Tanabe T. Ashwell G. J. Biol. Chem. 1977; 252: 8624-8628Abstract Full Text PDF PubMed Google Scholar). The mechanism of the neuraminidase inhibition of whole cell ASGPR activity is indirect; galactose residues exposed on cell glycoproteins block the lectin binding site on the ASGPR and inhibit exogenous TG binding (22Consiglio E. Salvatore G. Rall J.E. Kohn L.D. J. Biol. Chem. 1979; 254: 5065-5076Abstract Full Text PDF PubMed Google Scholar,42Paulson J.C. Hill R.L. Tanabe T. Ashwell G. J. Biol. Chem. 1977; 252: 8624-8628Abstract Full Text PDF PubMed Google Scholar).The role of the ASGPR in receptor-mediated endocytosis of asialoglycoproteins is well known (56Steer C.J. Ashwell G. Prog. Liver Dis. 1986; 8: 99-123PubMed Google Scholar, 57Geffen I. Speiss M. Int. Rev. Cytol. 1992; 137: 181-219Crossref Scopus (70) Google Scholar, 58Schwartz A.L. Targeted Diagn. Ther. Ser. 1991; 4: 3-39PubMed Google Scholar, 59Weigel P.H. Bergeron J.J.M. Harris J.R. Endocytic Components: Identification and Characterization. Plenum Publishing Corp., New York1993: 125-161Google Scholar). The present report establishes an additional role wherein binding of the ligand to the ASGPR regulates transcriptional events in the cell. Whether this function exists in other cells with an ASGPR and whether this involves regulation of tissue-specific or -restricted genes and cell function, i.e. in hepatocytes where its endocytotic role is clear, is unknown. Nevertheless," @default.
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W2149955916 title "Follicular Thyroglobulin (TG) Suppression of Thyroid-restricted Genes Involves the Apical Membrane Asialoglycoprotein Receptor and TG Phosphorylation" @default.
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